Phenylketonuria (PKU) is an inborn error of metabolism, which is characterized by marked reduction or complete absence of the activity of the phenyalanine hydroxylase (PAH) enzyme. In normal subjects, PAH catalyzes the conversion of L-phenyalanine (L-Phe) to L-tyrosine (L-Tyr). Loss of function of PAH in PKU patients results in dramatic accumulation of L-Phe in their blood and brain. L-Phe is neurotoxic at high concentrations and causes irreversible impairment of cognitive development in the PKU-afflicted subject.
In mammals, L-Phe is an essential amino acid that is not produced by the body and is derived solely from diet. The current therapy for PKU is a low-L-Phe-content synthetic diet that limits dietary L-Phe intake to less than 500 mg/day. Screening tests in newborns enables early identification of PKU and allows dietary treatment to begin before neurological damage occurs. Current guidelines require diet therapy to be continued for a lifetime. Unfortunately, the diet has unsatisfactory organoleptic properties that reduces compliance, especially in adolescents and adults, which may lead to impaired neurophysiological function. In pregnant PKU mothers, non-compliance results in increased fetal exposure to L-Phe, which is associated with a dramatic increase in fetal abnormalities. As another complication, the low-L-Phe-content synthetic diet is deficient in several nutrients, and may cause growth retardation, osteoporosis and even brain development problems. Failure to properly treat PKU patients may irreversibly compromise their full neurodevelopmental potential.
Alternative PKU therapies have been explored, such as gene therapy, but none of these strategies have led to a permanent correction of PAH activity. Gene therapy methods initially yield improved results, but patients eventually develop an immune response against the therapeutic vectors, leading to therapy rejection.
There is thus a need in the art for methods of treating PKU-afflicted patients. Such methods should avoid the drawbacks of the low-L-Phe-content diet and gene therapy based treatments. The present invention addresses this need.